Sex-specific impact of mild obesity on the prognosis of ST-segment elevation myocardial infarction

This study aimed to clarify the existence of the mild obesity paradox in patients with ST-segment elevation myocardial infarction (STEMI) and assess the impact of mild obesity on the prognosis of STEMI. A retrospective cohort study was conducted on STEMI patients who underwent percutaneous coronary intervention at Xiangtan Central Hospital from January 1, 2020 to July 31, 2022. After excluding individuals with a body mass index (BMI) of no less than 35 kg/m2, subjects were divided into the mildly obese group (BMI, 30–35 kg/m2) and non-obese group (BMI < 30 kg/m2). The cardiovascular events and death were deemed the composite endpoints and were employed as the outcome event. The study recruited 664 patients with STEMI, including 515 males and 149 females. The mildly obese group of male patients exhibited a lower incidence of composite endpoints than the non-obese group (22.4% vs. 41.3%, P < 0.001). For female patients, no significant difference was observed in the incidence of composite endpoints between the two groups (43.6% vs. 43.8%, P = 0.987). After adjusting for confounding factors, the multivariable Cox regression analysis revealed mild obesity as an independent protective factor for male patients [hazard ratio (HR) 0.47; 95% confidence interval (CI) 0.32–0.69; P < 0.001]. Nevertheless, mild obesity was not associated with the prognosis of female patients (HR 0.96; 95% CI 0.47–1.94; P = 0.9). In male STEMI patients, mild obesity presented a paradoxical effect in improving the prognosis and functioned as an independent protective factor for the prognosis of STEMI. However, no association between mild obesity and prognosis was found in female patients, possibly due to distinct physiological and metabolic characteristics between male and female patients, which deserved further investigation and validation.


Data collection and variable definitions
The patient's records were retrieved from the hospital's electronic medical record system and the national chest pain platform.These records comprised demographic information, past history, biochemical indicators at admission, medication usage, and PCI treatment-related details.During the specified study period, all eligible patients with STEMI and mild obesity in our center were consecutively included to ensure a systematic and fair selection of participants.

Independent risk factors associated with outcome events
We initially conducted univariate and multivariate analyses to investigate risk factors associated with outcome events.The findings are summarized below (Table 3).
Other factors, such as age, valvular heart disease, stroke, atrial fibrillation, and hypertension, emerged as risk factors for outcome events in the univariate analysis.However, their impacts were not statistically significant in the multivariate analysis.Besides, lipid-lowering drugs, ARBs, smoking, hyperlipidemia, alcohol consumption, COPD, hyperthyroidism, and ACEIs exhibited no significant association with outcome events in the univariate and multivariate analyses.

Stratified analysis
We conducted a comprehensive stratified analysis for multiple binary variables.Forest plots (Fig. 3) illustrated the relationship between mild obesity (independent variable) and composite endpoint events (dependent variable).The stratified analysis showed that mild obesity exerted a protective effect on the patient's prognosis in most subgroups, particularly under the following conditions: age ≥ 70 or < 70 years, smoker or non-smoker, non-drinker, with or without hyperlipidemia, with or without hypertension, without atrial fibrillation, with or without diabetes, without hyperthyroidism, with or without stroke, with or without valvular heart disease, without cardiomyopathy, without COPD, with or without renal insufficiency, and Killip classification ≥ 2 (all P < 0.05).In contrast, the association between mild obesity and composite endpoint events did not achieve statistical significance in subgroups of females, alcohol consumers, patients with atrial fibrillation, hyperthyroidism, cardiomyopathy, COPD, and Killip class I (all P values > 0.05).www.nature.com/scientificreports/ We carefully considered and analyzed numerous significant factors that might affect the prognosis of STEMI patients.To provide a comprehensive overview, we compared other important prognostic indicators between the mildly obese and non-obese groups (Supplementary Table 1).

Ethics approval and consent to participate
The study protocol was approved by the Ethics Committee of Xiangtan Central Hospital (Xiangtan, China, No. 2023-02-001) and conformed to the principles outlined in the Declaration of Helsinki.The need for informed consent was waived by the ethics committee Review Board of Xiangtan Central Hospital, because of the retrospective nature of the study.

Discussion
The study revealed that mild obesity functioned as an independent protective factor for the composite endpoint in male STEMI patients after adjusting for confounding variables.However, no association was identified between mild obesity and composite endpoint among female STEMI patients.Additionally, the administration of antiplatelet agents emerged as an independent protective factor for the incidence of the composite endpoint.
In contrast, a Killip class ≥ 2 and a history of cardiomyopathy were established as independent risk factors.
The fundamental similarity between this study and prior research validated the "obesity paradox" in obese patients, suggesting that obesity was correlated with a more favorable prognosis in particular CVD.Numerous investigations have demonstrated obesity as a significant risk factor for CVD, while obese patients exhibited a better prognosis than non-obese patients under specific circumstances, such as acute myocardial infarction and heart failure 1,5,14,17,18 .This phenomenon was known as the "obesity paradox".
The uniqueness of this study was that we further examined the influence of sex on the mild obesity paradox and revealed differences in the association of mild obesity with the prognosis of STEMI between male and female patients.Previous research has primarily concentrated on the mild obesity paradox, with less attention paid to the role of the sex factor 19,20 .In research focused on gender disparities in Acute Coronary Syndrome (ACS), there has been no observed trend supporting the obesity paradox 21 .Our investigation discovered a protective effect of mild obesity on male STEMI patients; however, this effect was not observed in female patients.This finding emphasized the importance of gender difference when assessing the impact of mild obesity on the prognosis of CVD and provided an innovative perspective for developing future interventions to address these differences.
This study suggested that the protective effect of mild obesity on the prognosis of male STEMI patients might be attributed to the following factors: (1) Obese patients were younger at onset and possessed a lower risk of CVD 6,22 ; (2) obese patients demonstrated excellent myocardial reserve function and resistance to myocardial ischemia 23 ; and (3) inflammatory factors and metabolic hormones in obese patients could have a protective effect on the myocardium 24 .In contrast, this protective effect was not present in female patients, possibly due to differences in the physiology, metabolism, diagnosis and treatment of coronary artery disease, characteristics of acute myocardial infarction, and coronary microvascular function associated with diabetes between male and female patients [25][26][27][28][29] .

Study limitations
The main limitations of this study included the following aspects: (1) The retrospective design of the study might lead to the bias of final results; (2) the sample size was relatively small, with a particularly limited number of females and patients with BMI ≥ 35 kg/m 2 ; (3) other metabolic indicators and hormone levels were not considered; (4) The limited racial diversity of the study cohort might affect the generalizability of our findings in other populations.To address these issues, future research should adopt a prospective design, increase the sample size, particularly the number of female patients, and further evaluate the impact of other metabolic indicators and hormone levels.

Clinical implications
To tackle the above limitations, we suggest future research directions as follows:

Conclusion
In conclusion, our study demonstrates that mild obesity is an independent protective factor for clinical outcomes in male patients with STEMI.Conversely, this protective effect was not observed in female patients.Further research is warranted to elucidate the underlying mechanism of our finding and develop potential sex-specific interventions to improve the prognosis of STEMI patients.

Figure 1 .
Figure 1.Flow diagram for participant screening, eligibility and analysis.

Figure 2 .
Figure 2. Trend plot of the composite endpoint for the mildly obese and non-obese groups.(A) Cumulative incidence of the composite endpoint in male.(B) Cumulative incidence of the composite endpoint in female.

( 1 )
Conduct prospective studies to minimize potential omissions and biases; (2) expand the research scope by increasing the sample size of female patients for a more comprehensive exploration of the impact of gender on the obesity paradox and incorporating patients with BMI ≥ 35 kg/m 2 to determine the cut-off value of BMI associated with the obesity paradox; (3) investigate the biological mechanisms of the impact of mild obesity on the prognosis of STEMI by taking into account factors like inflammation, metabolic hormones, and hormone levels; (4) Examine other interventions, including lifestyle change and medication treatments, to improve the prognosis of obese patients with CVD.

Figure 3 .
Figure 3. Forest plot: Relationship between mild obesity and composite endpoint events, stratified by multiple dichotomous variables based on obesity grouping.

Table 1 .
Baseline characteristics of mild obesity stratification after sex grouping.The population was classified according by obesity stratification after sex grouping.Values for continuous variables are given as means ± SD.Bold represent significant values (P < 0.05).

Table 2 .
Impact of mild obesity on clinical outcomes.Hazard ratios from Cox proportional hazards regressions.Model I adjust for: None.Model II adjust for: Age.Model III adjust for: Age; Smoker; Drinker; Hyperlipidemia; Hypertension; Atrial fibrillation; Diabetes mellitus; Hyperthyroidism; Stroke; Valvular heart disease; Cardiomyopathy; Chronic obstructive pulmonary disease; Renal insufficiency; Killip classification.

Table 3 .
Cox proportional hazards regression model analysis for risk of composite endpoint.Hazard ratios from Cox proportional hazards regressions.HR hazard ratio, CI confidence interval; Bold represent significant values (P < 0.05).